Ascorbic acid composition and method for treatment of aging or damaged skin

ABSTRACT

An ascorbic acid-based composition and related method for the treatment of aging or photo-damaged skin is disclosed. The composition includes water and ascorbic acid, at least a portion of which has generally been pretreated by being dissolved under relatively high temperature and concentration conditions. The composition typically includes at least about 5.0% (w/v) ascorbic acid and may advantageously be formulated to have a pH above 3.5. Generally, the composition also includes non-toxic zinc salt, tyrosine compound, and/or pharmaceutically acceptable carrier. In addition, the composition may include an anti-inflammatory compound, such as aminosugar and/or sulfur-containing anti-inflammatory compound. The topical composition may be in the form of a serum, a hydrophilic lotion, an ointment, a cream, or a gel.

This application is a continuation-in-part of U.S. provisionalapplication Ser. No. 60/125,356 (filed on Mar. 19, 1999), the disclosureof which is herein incorporated by reference.

BACKGROUND OF THE ART

Skin is composed of a top layer, the epidermis, which is approximately20 cell layers or about 0.1 mm in thickness, and a lower layer, thedermis, which is from about 1 to about 4 mm in thickness and containssmall blood vessels, collagen, elastin and fibroblasts. The dermisprovides structural support and nutrients to the epidermis. Aging hasbeen shown to increase cellular heterogeneity of the epidermal layer,however, it has little effect on the thickness of the epidermal layer.The supporting dermis, on the other hand, is known to thin with age andexposure to the sun and environmental contaminants. As the dermal layerprovides the support and blood supply for the epidermis, the dermallayer is important in maintaining the elasticity and appearance of theskin. Disruption of the supporting dermis leads directly to sagging andconsequent furrowing of the epidermis, i.e., the formation of wrinkles.

Deep wrinkles are also due to continual stretching and contraction ofboth the dermis and epidermis. Currently, these deep wrinkles or furrowsmay only be eliminated by plastic surgery or by collagen injectionsdirectly beneath the depressed areas. The fine wrinkles that occur withage and prolonged exposure to the sun and other environmentalcontaminants are the direct result of deterioration of the supportingdermal layer. Other environmental effects on the skin are discussed inU.S. Pat. No. 4,938,969 and U.S. Pat. No. 5,140,043, the disclosure ofwhich is herein incorporated by reference.

As a result of the aging process and damage caused by incidentradiation, a disruption of the collagen bundles that provide support tothe epidermis is observed. Collagen exists normally in dense, organizedpatterns. During the aging process collagen becomes disorganized andless supportive of the epidermis and the dermis loses elasticity. Thereis a also progressive loss of circulatory support from the small bloodvessels that are more numerous and close to the surface in young skin.The result of aging on skin, whether or not it has been accelerated byincident radiation, is a deterioration of the dermal layer—fewerfibroblasts, less collagen, less elastin and less circulatory support.Consequently, the normal stretching and contraction of the skin leads todamage of the dermis that is not readily corrected and wrinklingresults.

Dermatologists and cosmetologists have directed their efforts toimproving the appearance of skin using agents known to stimulate thegrowth and proliferation of epidermal cells. Newly proliferated cellsprovide more structure and hold more moisture, giving the skin a youngerappearance. One method of causing new skin cell proliferation isaccomplished by use of an irritant or chemical peel in which theuppermost layers of the epidermis are caused to slough off, leading toproliferation and replacement with new epidermal cells. While suchtreatment is recognized to provide some cosmetic improvement, it doesnot address the major causative factor—the compromised supporting dermallayer.

Considerable effort has also been expended to find ways to preventadverse changes in the skin brought about by ultraviolet (UV) exposure.Preventative approaches include physically blocking or absorbing the UVradiation before it can enter the skin using UV absorbing compounds.This technique is effective but is cumbersome because sunblockers orabsorbers must be applied before every exposure and may be washed offwith water. Thus, for example, after swimming UV absorbing compoundsmust typically be reapplied. Further, the long-term side effects of manyof the compositions containing sunblockers and/or absorbers are notknown.

L-ascorbic acid has many known biological functions from enzymaticco-factor to “sparing” agent against vitamin E depletion. See, forexample, Englard and Seifter, “The Biochemical Functions of AscorbicAcid,” Ann.Rev.Nutri. 6:365-406, (1986); Kunert and Tappel, “The Effectof Vitamin C on in vivo Lipid Peroxidation in Guinea Pigs as Measured byPentane and Ethane Production, Lipids 18:271-74 (1983). The latterfunction may partly account for its “anti-oxidant” status. Additionally,at higher concentrations, ascorbic acid is known to react with both thesuperoxide and hydroxyl radicals. Superoxide and the subsequentlygenerated hydrogen peroxide and hydroxyl radical are oxygen-containingfree radicals now known to be generated in vivo under a variety ofnormal and pathological conditions. These radicals have been implicatedas causative agents for everything from sunburn to aging and arebelieved to destroy lipid membranes, break down DNA, and inactivateenzymes, among other effects. An immense amount of work has been done inthe last two decades documenting the deleterious behavior of oxygenradicals. Several recent texts on the subject include: Oxy-radicals inMolecular Biology & Pathology, D. Cerutti, 1. Fridovich, J. McCord,eds., (Alan R. Liss, Inc. New York, 1988); Biological Role of ReactiveOxygen Species in Skin, O. Hayaishi, S. Inamura, Y. Mayachi, eds.(Elsevier Press, New York, 1987); Free Radicals, Aging and DegenerativeDiseases, J. E. Johnson, Jr., R. Walford, D. Harmon, J. Miguel, eds.(Alan Liss, Inc., New York, 1986); Free Radicals in Biology andMedicine, B. Halliwell and J. M. C. Gutteridge, eds. (Clarendon Press,Oxford, 1985); and Oxidative Stress Helmut Sies, ed. (Academic Press,1985). Also addressing the subject are several symposia, including“Oxygen Radicals and Tissue Injury” Proceedings from an Upjohn Symposium(April, 1987); and “Oxygen Free Radicals,” Proceedings from NationalHeart, Lung & Blood Institute (National Institute of Health, Washington,D.C., Dec. 1987).

As a result of the known effects of the use of ascorbic acid on damagedand aging skin, there are now various Vitamin C or ascorbic acidointments, serums and creams that are used with varying degrees ofsuccess to prevent and/or repair damage to the skin's dermal layer. Forexample, it has been reported that a composition including ascorbicacid, tyrosine and a non-toxic zinc salt, preferably zinc sulfate, in avehicle suitable for topical application, when applied to areas showingthe fine wrinkles associated with aging/sun exposure, results in areadily perceivable diminution of the fine wrinkle structure. It hasalso been reported that ascorbic acid topical aqueous compositions areunstable unless maintained at a pH below about 3.5. This documentindicated that topical compositions containing a carrier and aconcentration of L-ascorbic acid above about 1% (w/v) were stable ifmaintained at a pH below about 3.5, and preferably below about 2.5.

It has been found, however, that currently available ascorbic acidcompositions and methods fail to provide the delivery system forformulations having the desired combination of efficacy,non-irritability, stability and convenient storage solutions for topicalVitamin C applications. A significant problem of current compositions isthat it is not practical to use more than 15% (w/v) ascorbic acid in aserum, cream or gel formulation for cosmetic use because the lowinherent pH (circa 2-2.5) of such a formulation is often quiteirritating to the skin. The break-down of the ascorbic acid in such lowpH formulations due to exposure to water, heat, and air can also lead toundesirable discoloration and eventually loss of efficacy. Furthermore,if the ascorbic acid is formulated in a cream with limited water contentto enhance stability of the ascorbic acid over time, changes in heat,atmospheric pressure and/or moisture content may activate the ascorbicacid, leading to unacceptable expansion and even explosion of thecontainers holding such creams or gels. There is accordingly acontinuing need for topical ascorbic acid-based compositions thatimprove the efficacy and stability of such skin treatment formulations.

SUMMARY

The present invention provides stable, effective topical compositionswhich include ascorbic acid, generally in a relatively high pHformulation. The concentration of active ascorbic acid that is availableto be delivered to the skin is maintained at a high concentration, whileat the same time lowering the irritating effects commonly associatedwith aqueous compositions having a high concentration of organic acid.By providing, for example, a portion of the total ascorbic acid of thecomposition in the ascorbate salt form, the composition disclosed hereincan decrease the overall irritant nature of the solution without losingefficacy or desired biological effect. The present ascorbic acid-basedcomposition are particularly effective for topical application to reduceepidermal wrinkling, such as that resulting from intrinsic aging orphoto damage. For example, applying the present compositions withinabout six hours to skin that has received excess sun damage canattenuate the effects due to UV exposure and decrease sunburn and celldamage. In addition, the compositions disclosed herein did not expand orlose integrity on storage. The present compositions were also far lesslikely to oxidize to yield an off color (e.g., to become darker orbrown). Subjects using the present ascorbic acid formulations found theproduct to be very effective, and to yield rapid results relative todecreasing the appearance of fine lines.

The present compositions typically include up to about 50% of the totalascorbic acid present which has been prepared by dissolution in water atrelatively high temperature and concentration. Ascorbic acid which hasbeen dissolved in this manner is referred to herein as “pretreatedascorbic acid” and is prepared by dissolving a high concentration ofascorbic acid, typically at least about 20% (w/v) (i.e., at least about200 mg/ml) in water at 60 to 90° C.

Importantly, formulations containing 50% (w/v) of the ascorbic acidcontent of a cream in the form of the pretreated ascorbic acidformulated as described herein do not expand, explode, or discolor dueto heat, changes in atmospheric pressure, or improper storage, all ofwhich have proved to be problems in manufacturing, storing anddistributing formulations of pure L-ascorbic acid and its direct breakdown products.

Embodiments of the present compositions commonly include water, at leastabout 5.0% (w/v) ascorbic acid, and have a pH of more than 3.5.Preferably, the compositions have a pH of about 3.6 to about 4.2, and,more preferably, about 3.7 to 4.0. The compositions typically alsoinclude (a) non-toxic zinc salt and/or (b) a stimulant of proteinsynthesis and/or precursor to melanin synthesis (e.g., a tyrosinecompound). The compositions may also include an anti-inflammatorycompound, such as an aminosugar and/or a sulfur-containinganti-inflammatory compound. The topical compositions may be in any of anumber of common forms, such as an aqueous solution (“a serum”), ahydrophilic lotion-, an ointment-, a cream, or a gel. Typically, thetopical composition includes a pharmaceutically acceptable carrier andmay also include one or more other formulation additives, such assurfactant(s), thickener(s), other antioxidants and/or fragrance.

The “high pH” formulations of the present compositions are lessirritating than high concentrations of L-ascorbic acid (with itsinherent low pH, e.g., circa 2-2.5) because the relatively higher pHavoids the skin irritation problem often encountered with harsh chemicalpeels or solutions with pH values below 3.5. The present compositionswere also found to be very stable on short and long term storage, whilemaintaining a high degree of effectiveness.

The present invention also includes a method of treating damage to skin,such as often arises due ultraviolet light exposure and/or aging. Themethod includes applying the present topical composition to a damagedportion of the skin, For example, the present composition is typicallyapplied topically to the locus of wrinkles.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will become more fully understood from the followingdetailed description, taken in conjunction with the accompanyingdrawings, in which:

FIG. 1 shows a C13 NMR of a 10% (w/v) solution of “native” ascorbic acidafter storage for one week at 37° C.

FIG. 2 shows a C13 NMR of a 1:1 mixture of a 10% (w/v) solution of“native” ascorbic acid and a 30% (w/v) solution of “pretreated” ascorbicacid after storage of the mixture (at pH 2.3) for one month at roomtemperature.

FIG. 3 shows a C13 NMR of a 30% (w/v) solution of “pretreated” ascorbicacid after storage for one week at 37° C.

DETAILED DESCRIPTION

Long shelf-life and extended stability (e.g., for at least two years) isnormally required for any cosmetic product to be distributed throughordinary channels in which there must be stored inventory to meet marketdemand without the concern that the inventory will deteriorate beforebeing sold. The present ascorbic acid-based compositions have goodefficacy and storage stability, and low skin irritability. These topicalascorbic acid based compositions are particularly effective for reducingepidermal wrinkling resulting from intrinsic aging or photo damage. Thecompositions may also be used prophylactically to ameliorate thephoto-induced damage which can result from exposure of skin to sunlightand other harmful irradiation.

The compositions typically include at least about 5.0% (w/v) ascorbicacid. Herein, the amount of ascorbic acid present in a compositionrefers to the total amount of ascorbic acid and ascorbate present statedas if all was present in the acid form. In other words, a solution whichincludes 0.5 mole ascorbic acid and 0.5 mole of an ascorbate saltcontains the same total amount of ascorbic acid as a solutions whichinclude either 1.0 mole ascorbic acid or 1.0 mole of an ascorbate salt.

While the present compositions commonly include at least about 5.0%(w/v) total ascorbic acid, it is generally advantageous to includehigher concentrations, typically at least about 10% (w/v) and oftenconcentrations in the range of about 15 to about 25% (w/v) ascorbicacid. Because of the potential problems of skin irritation withformulations containing high concentrations of ascorbic acid, it isgenerally advantageous to adjust the pH of such formulations to at leastabout 3.5. To achieve an optimum combination of low irritability andhigh stability, the present compositions are typically formulated tohave a pH of about 3.7 to about 4.1 and, preferably, about 3.8 to about4.0.

It has found that ascorbic acid-based topical formulations in which asubstantial portion of the ascorbic acid has been “pretreated” exhibitparticularly good storage stability. As noted above, for the purposes ofthis application, pretreated ascorbic acid refers to ascorbic acid whichhas been dissolved in water at a relatively high temperature to form aconcentrated ascorbic acid solution. Typically, the ascorbic acid isdissolved in water at about 60 to about 90° C. (preferably about 75 toabout 80° C.) to form a concentrated solution which contains at leastabout 20% (w/v) ascorbic acid. During this pretreatment, the ascorbicacid is dissolved in the acid form, i.e., the resulting solution willhave a relatively low pH (circa 2.0-2.5). After dissolution, theconcentrate is generally heated for an additional period of time (e.g.,0.25 to 1.0 hour) and cooled to below about 40° C. before beingincorporated into the final formulation. If the pretreated concentrateis to be stored prior to formulation, it is preferably stored at roomtemperature or below (e.g., about 3 to about 20° C.) and/or underconditions which exclude oxygen-containing gases such as air (e.g., in asealed container or blanketed with an inert gas such as argon ornitrogen). In the present compositions, commonly at least about 10% ofthe ascorbic acid present has been pretreated. Typically, no more thanabout 50% of the ascorbic acid present has been pretreated. This allowsthe enhanced stability properties to be obtained while minimizing theadditional processing steps and cost associated with the pretreatment ofthe ascorbic acid.

To test and quantitate the stability of composition containing“pretreated” ascorbic acid, nuclear magnetic resonance (NMR) spectra ofstored samples of the following ascorbic acid-based solutions: (i) a 10%(w/v) solution of “native” ascorbic acid; (ii) a 1:1 mixture of the 10%(w/v) solution of “native” ascorbic acid and a 30% (w/v) solution of“pretreated” ascorbic acid; and (ii) the 30% (w/v) solution of“pretreated” ascorbic acid after storage. The results, shown in FIGS. 1,2 and 3 respectively, demonstrate the stability of the solutions understorage conditions. Somewhat accelerated storage testing is oftencarried out by storing solutions at 37° C. The results of tests (see,e.g., FIGS. 1 and 3) demonstrated that both a 10% (w/v) solution of“native” ascorbic acid and a 30% (w/v) solution of “pretreated” ascorbicacid were stable after storage at 37° C. for one week.

As an example, containers having a 1 to 20% (w/v) concentration of amixture of pretreated ascorbic acid in a 1:1 to 1:10 ratio, togetherwith ascorbic acid formulated under more standard conditions (i.e.,dissolved or added in solid form to a formulation at temperatures ofabout 20 to about 40° C.—“native ascorbic acid”) were quite stable whenshipped and/or stored under adverse conditions, or even when heated. Thestability of such formulations was enhanced in comparison toconventional low pH formulations containing untreated ascorbic acid,e.g., low pH creams containing 10% (w/v) untreated ascorbic acid.

The present compositions generally also include a non-toxic zinc salt.The zinc salt is preferably a water soluble zinc salt such as zincsulfate. The zinc salt is generally present in about 0.5 to about 5.0%(w/v). Very effective results can typically be obtained withcompositions which include no more than about 3.0% (w/v) zinc salt. Forexample, a number of present compositions are commonly formulated withabout 0.5 to about 2.0% (w/v) zinc sulfate together with the othercomponents described herein.

The composition of the present invention may further include one or morecompounds capable of serving as a stimulant of protein synthesis and/orprecursor to melanin synthesis. This component is generally present inabout 1 to about 10% (w/v), and more preferably 3 to about 8% (w/v),based on the total composition. Typically, this component includes atyrosine compound. As employed herein, a “tyrosine compound” is tyrosineor a compound which is capable of generating tyrosine upon chemicaland/or biological transformation. Examples of suitable tyrosinecompounds for use in the present compositions include tyrosine,N-acetyl-tyrosine, tyrosine ethyl ester hydrochloride, and tyrosinephosphate.

The present compositions may also include a compound which can functionas an anti-inflammatory agent. Examples of suitable anti-inflammatoryagents include anti-inflammatory sulfur-containing compounds andanti-inflammatory aminosugars. The sulfur-containing anti-inflammatorycompound is typically a sulfur containing amino acid or relatedderivative such as cystine, cysteine, N-acetyl cysteine, glutathione,cysteamine, S-methylcysteine, methionine and the like. Examples ofsuitable anti-inflammatory aminosugars include glucosamine, mannosamine,N-acetylmannosamine, galactosamine, glucosamine-6-phosphate,N-acetylglucosamine, N-acetylmannosamine, N-acetylgalactosamine and thelike. For example, by adding D-glucosamine hydrochloride to the presentcompositions (in circa 5-20% (w/v)), cellular damage due to excess sunexposure can be minimized even if applied roughly 12 hours afterexposure due to the anti-inflammatory effects of glucosamine in concertwith ascorbic acid.

The ascorbic acid and tyrosine compound components of the presentcompositions may be formulated in part or whole in a neutralized or saltform. Acceptable amine salts include the acid addition salts (e.g.,formed with a free amino group of a tyrosine compound) and may be formedwith inorganic acids such as, for example, hydrochloric or phosphoricacids, or such organic acids as acetic, oxalic, tartaric, mandelic, andthe like. Salts formed with the free carboxyl groups may also be derivedfrom inorganic bases such as, for example, sodium, potassium, ammonium,calcium, or ferric hydroxides, and such organic bases as isopropylamine,trimethylamine, histidine, procaine and the like. As noted elsewhereherein, since the present compositions have a pH of 3.5 or above (andtypically at least about 3.7) the ascorbic acid is typically at leastpartially present in the form of ascorbate salt(s). Commonly, the pH ofthe composition is adjusted to the desired value by adding sufficientbase, such as sodium hydroxide, potassium hydroxide and/or ammoniumhydroxide, to achieve the desired value. In such situations, theascorbate would exist at least in part in the form of sodium hydroxide,potassium and/or ammonium ascorbate.

The water used for preparing the compositions of the present inventionmay be distilled and/or deionized, but any water may be used that doesnot contain contaminants which would affect the stability of theascorbic acid present in the composition. For example, the presence ofcertain metal ions such as copper and iron salts, is known to effect thestability of ascorbic acid. The effects of water of varying purity onascorbic acid stability is discussed in Meucci, et al., “Ascorbic AcidStability in Aqueous Solutions,” Acta Vitaminol. Enzymol. 7(34): 147-54(1985), the disclosure of which is incorporated herein by reference.

The present compositions typically also include a pharmaceuticallyacceptable carrier. Carriers for topical application useful inpracticing the invention include, but are not limited to,alkyleneglycols, or alkyleneglycols in combination with one or morederivatives of hydroxyalkylcellulose. In one illustrative embodiment,the alkylene glycol is propyleneglycol and the hydroxyalkylcellulose ishydroxypropylcellulose. When a combination of alkyleneglycol andhydroxyalkylcellulose is used, a useful ratio of alkyleneglycol tohydroxyalkylcellulose is from about 30:1 to 5:1. Without limitation,other carriers known to those skilled in the art that are compatiblewith water and are biologically acceptable are expected to provideequivalent compositions within the scope of this invention. For example,alcohols such as ethanol and propanol, glycols such as butylene orhexylene glycol, and polyols such as sorbitol or glycerol may besuitably employed. Other examples of suitable carriers includepolyethylene or polypropylene glycols. Also contemplated as carriers foruse in the present compositions are biologically acceptablehydroxyalkylcelluloses.

The phrase “pharmaceutically acceptable” refers to molecular entitiesand compositions that do not produce an allergic or similar untowardreaction when administered to a human. The pharmaceutically acceptablecarriers and additives employed in the present compositions arecompatible with at least one formulation of the ascorbic acid/ascorbatemixture, tyrosine compound and zinc salt containing compositions asdescribed herein.

Amino acids employed in the present compositions will generally be inthe left-handed chiral form of the amino acid (i.e., L-amino acid(s)).The amino acids should be as pyrogen free as possible and should meetsterility, pyrogenicity, general safety and purity standards as requiredby FDA Office of Drug standards. The amino acids may even act as buffersfor the present solutions or may even be used to adjust the pH of thesolution to above 3.5. Illustrative examples of the present compositionscan be produced as follows. The appropriate amounts of the acid forms ofnative and untreated ascorbic acid are mixed and/or dissolved in water.A water soluble, non-toxic zinc salt is then added and the mixture ismixed (via stirring or agitation) until the zinc salt has dissolved.Other components, such a tyrosine compound and/or anti-inflammatorycompound(s) are then added if desired. After the other ingredients havebeen added to the solution, the pH is adjusted by adding an appropriateamount of a base such as sodium hydroxide or sodium carbonate to producea pH of about 3.8 to about 4.0. The resulting solution can be employedas a topical composition in this form (i.e., a “serum”) or may be usedto produce any of a variety of conventional formulations well known tothose skilled in the art, e.g., as a cream, lotion or gel.

The present topical composition may be in the form of an aqueoussolution (i.e., “serum”) or blended into a tissue compatible vehicle,such as hydrophilic lotion-, ointment-, cream- or gel-based vehicle.Such vehicles are well known in the art and commercially available forformulation of active ingredients into a suitable form for topicalapplication. Exemplary of such vehicles are the commercially availableDermabase and Unibase formulations.

The present composition can include one or more of a variety of optionalingredients, such as coloring agents, opacifying agents and the like.The formulation can include, in addition to the components describedhereinabove, other active ingredients, such as antibiotics, analgesics,anti-allergenics and the like. The formulation is commonly applied tothe skin as a lotion or cream to be rubbed on body tissue over thedesired area. For optimum efficacy treatment in accordance with thepresented method should be initiated as early as possible followingexposure to sunlight or another radiation source. The formulation isgenerally applied to the skin once or twice daily. As noted elsewhereherein, the present composition may also be used to inhibit the effectsof aging and/or photo damage on the skin.

Administration

Upon formulation, solutions will be administered in a manner compatiblewith the dosage formulation and in such amount as is therapeuticallyeffective. The formulations are easily administered in a variety ofdosage forms such as direct topical application, application via atransdermal patch and the like.

For topical administration in an aqueous solution, for example, theascorbic acid/ascorbate mixture, tyrosine compound and zinc saltcontaining compositions may be used directly on the skin without anytoxic effects to the animal or patient. Alternatively, the ascorbicacid/ascorbate mixture, tyrosine compound and zinc salt containingcompositions identified herein, may be dissolved or resuspended in asuitable buffer prior to mixing, if necessary. Liquid diluents may firstbe rendered isotonic with sufficient saline or glucose solutions.

The present aqueous solutions are especially suitable for topicaladministration. As discussed above, however, other ascorbic acid-basedformulations may also be used quite effectively. Some variation indosage will necessarily occur depending on the condition of the subjectbeing treated. The person responsible for administration will, in anyevent, determine the appropriate dose for the individual subject.Moreover, for human administration, preparations should meet sterility,pyrogenicity, general safety and purity standards as required by FDAOffice of Biologics standards.

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts whichcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention. Various modifications and combinations of the illustrativeembodiments, as well as other embodiments of the invention, will beapparent to persons skilled in the art upon reference to thedescription.

What is claimed is:
 1. A topical composition comprising: at least about5.0% (w/v) ascorbic acid; water; nontoxic zinc salt; and tyrosinecompound; wherein the composition bas a pH which is adjusted to about3.6 to about 4.2 by adding a sufficient amount of base; and at leastabout 10 wt. % of the total ascorbic acid is pretreated ascorbic acid,and the pretreated ascorbic acid is produced by dissolving at leastabout 20% (w/v) ascorbic acid in water at 60 to 90° C.
 2. Thecomposition of claim 1 wherein the composition has a pH of about 3.7 toabout 4.0.
 3. The composition of claim 1 further comprising ananti-inflammatory compound.
 4. The composition of claim 3 wherein theanti-inflammatory compound includes sulfur-containing anti-inflammatorycompound.
 5. The composition of claim 4 wherein the sulfur-containinganti-inflammatory compound is selected from the group consisting ofcystine, cysteine, N-acetyl cysteine, glutathione, cysteamine,S-methylcysteine, methionine and mixtures thereof.
 6. The composition ofclaim 3 wherein the anti-inflammatory compound includes aminosugar. 7.The composition of claim 6 wherein the aminosugar includes glucosamine,mannosamine, galactosamine, glucosamine-6-phosphate,N-acetylglucosamine, N-acetylmannosamine, N-acetylgalactosamine andmixtures thereof.
 8. The composition of claim 1 wherein the ascorbicacid is present in an amount of about 15% (w/v) to about 25% (w/v). 9.The composition of claim 1 wherein the water is selected from the groupconsisting of distilled water, deionized water, distilled deionizedwater and mixtures thereof.
 10. The composition of claim 1 wherein thenon-toxic zinc salt is present in an amount of about 0.5 to about 5%(w/v).
 11. The composition of claim 1 wherein the non-toxic zinc salt iszinc sulfate.
 12. The composition of claim 1 wherein the tyrosinecompound is selected from the group consisting of tyrosine,N-acetyl-tyrosine, tyrosine ethyl ester hydrochloride, tyrosinephosphate and mixtures thereof.
 13. The composition of claim 1 whereinthe tyrosine compound is present in an amount of about 1 to about 10%(w/v).
 14. The composition of claim 1 further comprising apharmaceutically acceptable carrier.
 15. The composition of claim 14wherein the pharmaceutically acceptable carrier includes glycerol,propyleneglycol, sorbitol, hydroxypropylcellulose or a mixture thereof.16. The composition of claim 14 wherein the pharmaceutically acceptablecarrier includes alkyleneglycol, hydroxyalkylcellulose or a mixturethereof.
 17. A topical composition comprising: an aqueous solutioncomprising at least about 5% (w/v) ascorbic acid, wherein at least about10 wt. % of the total ascorbic acid is pretreated ascorbic acid, and thepretreated ascorbic acid is produced by dissolving at least about 20%(w/v) ascorbic acid in water at 60 to 90° C.; tyrosine compound; andnon-toxic zinc salt; wherein the composition has a pH which is adjustedto about 3.6 to about 4.2 by adding a sufficient amount of base.
 18. Thecomposition of claim 17 wherein the ascorbic acid is present in anamount of about 15 to about 25% (w/v) and said composition a pH of about3.7 to about 4.0.
 19. The composition of claim 17 wherein the tyrosinecompound is present in an amount of about 1 to about 10% (w/v) and thenon-toxic zinc salt is present in an amount of about 0.5 to about 5%(w/v).
 20. The composition of claim 17 further comprising ananti-inflammatory compound which includes sulfur-containinganti-inflammatory compound, aminosugar or a mixture thereof.
 21. Atopical composition comprising: an aqueous solution comprising at leastabout 5.0% (w/v) ascorbic acid, wherein about 10 to about 50 wt. % ofthe total ascorbic acid is pretreated ascorbic acid, and the pretreatedascorbic acid is prepared by dissolving at least about 20% (w/v)ascorbic acid in water at 60 to 90° C.; tyrosine compound; and non-toxiczinc salt; wherein the composition has a pH which is adjusted to about3.6 to about 4.2 by adding a sufficient amount of base.
 22. Thecomposition of claim 21 wherein the aqueous solution has a pH of about3.7 to about 4.0.
 23. The composition of claim 21 wherein the non-toxiczinc salt is present in an amount of about 0.5 to about 5% (w/v). 24.The composition of claim 21 wherein the tyrosine compound is present inan amount of about 1.0 to about 10% (w/v).
 25. The composition of claim21 further comprising a precursor of melanin synthesis other than saidtyrosine compound.
 26. The composition of claim 21 wherein the ascorbicacid is present in an amount of about 15 to about 25% (w/v).
 27. Amethod of treating damage to skin comprising applying a topicalcomposition to the skin, wherein the topical composition comprises: atleast about 5.0% (w/v) ascorbic acid; water; non-toxic zinc salt; andtyrosine compound; wherein the composition has a pH which is adjusted toabout 3.6 to about 4.2 by adding a sufficient amount of base; and atleast about 10 wt. % of the total ascorbic acid is pretreated ascorbicacid, and the pretreated ascorbic acid is produced by dissolving atleast about 20% (w/v) ascorbic acid in water at 60 to 90° C.
 28. Themethod of claim 27 wherein the topical composition is applied to theskin once or twice daily.
 29. The method of claim 27 wherein the topicalcomposition is an aqueous solution, a lotion, an ointment, a cream, or agel.
 30. A method of treating damage to skin comprising applying atopical composition to the skin the topical composition comprising anaqueous solution including at least about 5.0% (w/v) ascorbic acid,wherein about 10 to about 50 wt. % of the total ascorbic acid ispretreated ascorbic acid, and the pretreated ascorbic acid is preparedby dissolving at least about 20% (w/v) ascorbic acid in water at 60 to90° C.; tyrosine compound; and non-toxic zinc salt; wherein thecomposition has a pH which is adjusted to about 3.6 to about 4.2 byadding a sufficient amount of base.
 31. The method of claim 30 whereinthe non-toxic zinc salt is present in an amount of about 0.5 to about 5%(w/v) and the tyrosine compound is present in an amount of about 1.0 toabout 10% (w/v).
 32. A method of protecting skin against damage due toexposure to radiation or chemicals comprising applying a topicalcomposition to the skin, wherein the topical composition comprises: atleast about 5.0% (w/v) ascorbic acid; water; non-toxic zinc salt; andtyrosine compound; wherein the composition has a pH which is adjusted toabout 3.6 to about 4.2 by adding a sufficient amount of base; and atleast about 10 wt. % of the total ascorbic acid is pretreated ascorbicacid, and the pretreated ascorbic acid is produced by dissolving atleast about 20% (w/v) ascorbic acid in water at 60 to 90° C.
 33. Amethod of protecting skin against damage due to exposure to radiation orchemicals comprising applying a topical composition to the skin, thetopical composition comprising non-toxic zinc salt; tyrosine compound;and an aqueous solution including at least about 5.0% (w/v) ascorbicacid, wherein about 10 to about 50 wt. % of the total ascorbic acid ispretreated ascorbic acid, and the pretreated ascorbic acid is preparedby dissolving at least about 20% (w/v) ascorbic acid in water at 60 to90° C. and the composition has a pH which is adjusted to about 3.6 toabout 4.2 by adding a sufficient amount of base.
 34. The method of claim33 wherein the radiation includes ultraviolet radiation.
 35. The methodof claim 33 wherein the non-toxic zinc salt is present in an amount ofabout 0.5 to about 5% (w/v) and the tyrosine compound is present in anamount of about 1.0 to about 10% (w/v).